This invention relates to quaternary ammonium compounds. More particularly, this invention relates to 1-(2-acylimidazol-1-ylalkyl)quinuclidinium salts and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such salts.
The present compounds are antagonists of tachykinins, including NKA (neurokinin A), NKB (neurokinin B) and Substance P, acting at the human neurokinin-1(NK1), neurokinin-2 (NK2) and neurokinin-3 (NK3) receptors.
These compounds are particularly useful as dual NK1 and NK2 receptor antagonists and can therefore be used for treating an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastro-intestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn""s disease, a disease caused by Helicobacter pylori or another urease-positive Gram negative bacteria, a urogenital tract disorder such as incontinence, impotence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a proliferative disorder such as a cancer or a disorder involving fibroblast proliferation, a vasospastic disease such as angiogenesis, angina or Reynaud""s disease, a fibrosing or collagen disease such as atherosclerosis, scleroderma or eosinophilic fascioliasis, reflux sympathetic dystrophy such as shoulder/hand syndrome, an addiction disorder such as alcoholism, a stress-related somatic disorder, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, a neuropathological disorder such as Alzheimer""s disease or multiple sclerosis, a disorder related to immune enhancement or suppression such as systemic lupus erythematosis, a rheumatic disease such as fibrositis, emesis, cough, acute or chronic pain, migraine, an ophthalmic disease such as proliferative retinopathy, influenza or a cold.
EP-A-680962 and EP-A-0739891 disclose heterocyclic compounds which are non-peptide antagonists of NKA and that are useful for the treatment of diseases such as asthma. EP-A-0591040 discloses quaternary compounds with tachykinin antagonist activity.
The present invention provides compounds of the formula: 
wherein
R is phenyl, C3-C7 cycloalkyl or heteroaryl, each of which being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy, C2-C4 alkanoyl, halo, C1-C4 alkoxycarbonyl, C3-C7 cycloalkyl, xe2x80x94S(O)m(C1-C4 alkyl), cyano, xe2x80x94NR2R3, xe2x80x94S(O)mNR2R3, xe2x80x94NR4(C1-C4 alkanoyl) and xe2x80x94CONR2R3, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl;
R1 is H or C1-C6 alkyl;
R2 and R3 are either each independently selected from H and C1-C6 alkyl, or when taken together, represent C4-C6 alkylene;
R4 is H or C1-C6 alkyl;
W is a direct link, methylene or ethylene;
X is unbranched C2-C4 alkylene;
Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7 cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, halo and cyano;
Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan4 or 5-yl or 1,4-benzodioxan-5 or 6-yl;
m is 0, 1 or 2;
ZA is a pharmaceutically acceptable anion;
and xe2x80x9cheteroarylxe2x80x9d, used in the definition of R, means thienyl or a 5- or 6-membered ring heteroaryl group containing either from 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatom(s) and 1 oxygen or sulphur heteroatom,
with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group.
In the above definitions, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo and alkyl and alkoxy groups having three or more carbon atoms, alkanoyl groups having four carbon atoms and alkylene groups having two or more carbon atoms (except where stated) may be unbranched- or branched-chain.
ZA is a pharmaceutically acceptable anion such as chloride, bromide, nitrate, methanesulphonate, para-toluenesulphonate, benzenesulphonate, hydrogen sulphate or sulphate.
Preferably, ZA is chloride or methanesulphonate.
Most preferably, ZA is methanesulphonate.
A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid.
Preferably, R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy and halo, or R is 2,3-dihydrobenzo[b]furanyl.
More preferably, R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl.
Yet more preferably, R is phenyl, naphthyl or tetrahydronaphthyl, each of which being optionally substituted by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl.
Yet further preferably, R is phenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2-trifluoromethoxyphenyl, 2-methoxy-3-methylphenyl, 2,3-dihydrobenzo[b]furan-7-yl, naphth-2-yl, 4-fluoro-3-trifluoromethylphenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 5-chloro-2-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-isopropoxyphenyl, 2-ethylphenyl, 2-phenoxyphenyl or 3,5-bis(trifluoromethyl)phenyl.
Most preferably, R is 2,3-dimethylphenyl, naphth-2-yl, 1,2,3,4-tetrahydronaphth-5-yl or 2-methoxyphenyl.
Preferably, R1 is H.
Preferably, W is a direct link or methylene.
Most preferably, W is a direct link.
Preferably, X is 1,2-ethylene.
Preferably, Y is phenyl, naphthyl or cyclohexyl, each of which being optionally substituted by 1, 2 or 3 C1-C4 alkyl substituents.
More preferably, Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphth-2-yl.
Most preferably, Y is phenyl.
Preferably, Ar is phenyl optionally substituted by 1, 2 or 3 halo substituents.
More preferably, Ar is phenyl substituted by 1 or 2 chloro substituents.
Most preferably, Ar is 3,4-dichlorophenyl.
Preferred examples of compounds of the formula (I) are compounds of the formula: 
wherein
1) Rxe2x80x94Wxe2x80x94 is 3,5-dimethylphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
2) Rxe2x80x94Wxe2x80x94 is 2,3-dimethylphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
3) Rxe2x80x94Wxe2x80x94 is 2-trifluoromethoxyphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
4) Rxe2x80x94Wxe2x80x94 is 2-methoxy-3-methylphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
5) Rxe2x80x94Wxe2x80x94 is 2,3-dihydrobenzo[b]furan-7-yl, Y is phenyl and ZA is CH3SO3xe2x88x92;
6) Rxe2x80x94Wxe2x80x94 is naphth-2-yl, Y is phenyl and ZA is CH3SO3xe2x88x92;
7) Rxe2x80x94Wxe2x80x94 is 4-fluoro-3-trifluoromethylphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
8) Rxe2x80x94Wxe2x80x94 is 1,2,3,4-tetrahydronaphth-5-yl, Y is phenyl and ZA is CH3SO3xe2x88x92;
9) Rxe2x80x94Wxe2x80x94 is 1,2,3,4-tetrahydronaphth-6-yl, Y is phenyl and ZA is CH3SO3xe2x88x92;
10) Rxe2x80x94Wxe2x80x94 is 5-chloro-2-methoxyphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
11) Rxe2x80x94Wxe2x80x94 is 2-methoxyphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
12) Rxe2x80x94Wxe2x80x94 is 2-trifluoromethylphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
13) Rxe2x80x94Wxe2x80x94 is 2-isopropoxyphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
14) Rxe2x80x94Wxe2x80x94 is 2-ethylphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
15) Rxe2x80x94Wxe2x80x94 is 2-phenoxyphenyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
16) Rxe2x80x94Wxe2x80x94 is benzyl, Y is phenyl and ZA is CH3SO3xe2x88x92;
17) Rxe2x80x94Wxe2x80x94 is 3,5-bis(trifluoromethyl)phenyl, Y is phenyl and ZA is Clxe2x88x92;
18) Rxe2x80x94Wxe2x80x94 is 2-methoxyphenyl, Y is cyclohexyl and ZA is CH3SO3xe2x88x92;
19) Rxe2x80x94Wxe2x80x94 is 4-fluoro-3-trifluoromethylphenyl, Y is cyclohexyl and ZA is CH3S3xe2x88x92;
20) Rxe2x80x94Wxe2x80x94 is 2-methoxyphenyl, Y is 3,5-dimethylphenyl and ZA is CH3SO3xe2x88x92; or
21) Rxe2x80x94Wxe2x80x94 is 2-methoxyphenyl, Y is naphth-2-yl and ZA is CH3SO3xe2x88x92: or an alternative pharmaceutically acceptable salt of any thereof (re ZA).
Particularly preferred examples of the compounds of the formula (I) are 4-phenyl-1-(3(S)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)-imidazol-1-yl]butyl)quinuclidinium methanesulphonate and 4-phenyl-1-(3(R)-[3,4-dichlorophenyl]4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate.
All the compounds of the formula (I) can be prepared by reaction of a compound of the formula: 
wherein R, R1, Ar, W and X are as previously defined for a compound of the formula (I), Z is a suitable leaving group capable of forming a pharmaceutically acceptable anion (ZA) and Z1 is a suitable leaving group, with a compound of the formula: 
wherein Y is as previously defined for a compound of the formula (I), said process being followed by either (a), where Z1 is a suitable leaving group, exchange for a pharmaceutically acceptable anion (ZA), or (b), optionally, where ZA is a pharmaceutically acceptable anion, exchange for another pharmaceutically acceptable anion.
Preferred examples of Z are C1-C4 alkanesulphonyloxy, benzenesulphonyloxy, para-toluenesulphonyloxy, chloro, bromo and iodo.
An example of Z1 is trifluoromethanesulphonyloxy.
Preferably, the leaving group in the compound of the formula (II) forms a pharmaceutically acceptable anion (Z/ZA), e.g. methanesulphonyloxy/methanesulphonate, and therefore anion exchange at the end of the process is unnecessary.
It is possible to exchange pharmaceutically acceptable anions (re ZA) in the work-up procedure, e.g. methanesulphonate may be exchanged to chloride by treatment of the isolated compound or the crude mixture with aqueous hydrochloric acid solution.
The reaction of the compounds (II) and (III) is generally carried out in a suitable solvent, e.g. acetonitrile, at elevated temperatures, preferably at the reflux temperature thereof.
The starting materials of the formula (II) can be prepared as shown in Scheme 1. 
wherein R, R1, Ar, W, X, Z and Z1 are as previously defined for a compound of the formula (II) and L and L1 are suitable leaving groups, e.g. chloro, bromo, iodo, methanesulphonyloxy, trifluoromethanesulphonyloxy, benzenesulphonyloxy and para-toluenesulphonyloxy.
Suitable reaction conditions, reagents and solvents for carrying out any one of the steps shown in Scheme 1 will be well-known to those skilled in the art with reference to the Preparations herein.
With regard to the last step in the reaction sequence, a compound of the formula (XV) can be converted to a compound of the formula (II) using conventional conditions. For example, an alcohol of the formula (XV) can be converted to a compound of the formula (II) where Z is methanesulphonyloxy by treatment with methanesulphonyl chloride, triethylamine and dichloromethane, and a compound of the formula (II) wherein Z1 is trifluoromethanesulphonyloxy may be prepared by treating an alcohol of the formula (XV) with trifluoromethanesulphonic anhydride, optionally in the presence of a suitable acid acceptor, and in a suitable solvent, e.g. dichloromethane.
The compounds of the formula (XII) can also be prepared as shown in Scheme 2: 
wherein R1 and Ar are as previously defined for a compound of the formula (XII) and L2 and L3 are suitable leaving groups, e.g. as previously defined for L and L1.
Suitable reaction conditions, reagents and solvents for carrying out any one of the steps shown in Scheme 2 will be well-known to those skilled in the art with reference to the Preparations herein.
The compounds of the formula (XV) can also be prepared as shown in Scheme 3: 
wherein R, R1, Ar, W and X are as previously defined for a compound of the formula (XV), L4 and L5 are suitable leaving groups, e.g. as defined for L and L1, and P is a suitable protecting group.
Examples of suitable protecting groups (P) together with methods for their removal can be found in the publication xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, T. W. Greene and P. G. M. Wuts, Second Edition, Wiley-Interscience. A preferred example of P is tetrahydropyran-2-yl that can be removed using Amberlyst 15 (trade mark) ion exchange resin or methanol saturated with hydrogen chloride gas.
Suitable reaction conditions, reagents and solvents for carrying out any one of the steps shown in Scheme 3 will be well known to those skilled in the art with reference to the Preparations herein.
The compounds of the formula (XXXI) can also be prepared by reacting a compound of the formula (XXIX) with a compound of the formula: 
wherein R and W are as previously defined for a compound of the formula (XXXI), optionally in the presence of an additional acid acceptor, e.g. potassium carbonate.
The compounds of the formula (XXXII) may be prepared as shown in Scheme 4. 
wherein R and W are as previously defined for a compound of the formula (XXXII).
The compounds of the formula (III) can be prepared by a similar method to that described in Chem.Ber., 108, 3475 (1975).
Alternatively, the compounds of the formula (III) where Y is cyclohexyl optionally substituted as previously defined for the definition of Y for a compound of the formula (I) can be prepared by catalytic hydrogenation of a compound of the formula: 
wherein Y is phenyl optionally substituted as previously defined for the above definition of Y. The reduction can be carried out under a hydrogen atmosphere using a suitable catalyst, e.g. rhodium-on-alumina, and in a suitable solvent, e.g. acetic acid.
The compounds of the formula (IIIA) may be prepared by similar methods to those described in Chem.Ber., 108, 3475 (1975) and J.Org.Chem., 22, 1484 (1957).
The compounds of the formula (III) can also be prepared as shown in Scheme 5: 
wherein Y is as previously defined for a compound of the formula (III).
Suitable reaction conditions, reagents and solvents for carrying out any one of the steps shown in Scheme 5 will be well-known to those skilled in the art with reference to the Preparations herein.
All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.
The affinity of the compounds of the formula (I) for the human NK1 receptor can be determined in vitro by determining their ability to inhibit [3H]-Substance P binding to membranes prepared from the human IM9 cell line expressing the human NK1 receptor using a modification of the method described in McLean, S. et al, J. Pharm.Exp.Ther., 267, 472-9 (1993) in which whole cells were used.
The affinity of the compounds of formula (I) for the human NK2 receptor can be determined in vitro by determining their ability to compete with [3H]-NKA (neurokinin A) for binding to membranes prepared from Chinese hamster ovary cells expressing the cloned human NK2 receptor. In this method, washed Chinese hamster ovary cell membranes are prepared as described for the previous method where IM9 cells are used instead. The membranes are incubated (90 min, 25xc2x0 C.) with [3H]-NKA and with a range of concentrations of the test compound. Non-specific binding is determined in the presence of 10 xcexcM NKA.
The NK1 receptor antagonist activity of the compounds of the formula (I) can be determined in vitro by testing their ability to antagonise the contractile effects of Substance P in de-epithelialised guinea pig tracheal strips. Tissues can be prepared from guinea pigs (350-600 g) which are killed by stunning and exsanguination. The excised trachea is cleared of connective tissue and opened longitudinally, opposite the trachealis muscle band. The epithelial layer can then be removed by rubbing the inner surface of the trachea with a cotton bud. Strips of approximately 4 cartilage bands wide are cut and mounted under 1 g tension in organ baths containing Krebs solution (composition: NaCl 118 mM, KCl 4.6mM, NaHCO3 25 mM, KH2PO4 1.4 mM, MgSO4 1.2 mM, CaCl2 2.5 mM, glucose 11 mM) at 37xc2x0 C. and gassed with 95% O2/5% CO2. The potential action of Substance P on the NK2 receptor population found in this tissue can be prevented by the inclusion of the selective NK2 receptor antagonist xc2x1SR-48,968 (1 xcexcM) in the Krebs buffer solution. Additionally, indomethacin (3 xcexcM) is added to remove the influence of endogenous prostanoids. Tension changes of the tissue in response to cumulative addition of the agonist Substance P are recorded isometrically. The potency of the compounds of the formula (I) can be assessed by the magnitude of shift induced in the Substance P dose response curve, using standard Schild analysis, following 30 minutes incubation of the compound with the tissue.
The de-epithelialised guinea pig trachea strip preparation may also be used to evaluate the NK2 receptor antagonist activity of the compounds of the formula (I) in vitro by using the selective NK2 receptor agonist [xcex2-Ala8]NKA(4-10) as the contractile agent. For such studies, strips are prepared and mounted in organ baths as described above, using Krebs solution of the following composition: NaCl 118 mM, KCl 4.6 mM, NaHCO3 25 mM, KH2PO4 1.4 mM, MgSO4 1.2 mM, CaCl2 2.5 mM, glucose 11 mM, indomethacin 3 xcexcM. The potency of the compounds may be assessed by the magnitude of the shift induced in the [xcex2-Ala8]NKA(4-10) dose response curve, using standard Schild analysis, following 30 minutes incubation of the compound with the tissue.
The compounds of the formula (I) can be tested for NK3 receptor antagonist activity, in vitro, by testing their ability to antagonise the contractile effects of the selective NK3 receptor agonist senktide in the guinea-pig ileum using the method of Maggi et al, Br.J.Pharmacol., 101, 996-1000 (1990).
For human use, the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, they can be administered orally or sublingually in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will be from 0.01 to 20 mg/kg (in single or divided doses).
Thus tablets or capsules of the compounds will contain from 1 mg to 1.0 g of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container or a nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
Aerosol formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains from 20 xcexcg to 1000 xcexcg of a compound of formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20 xcexcg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated, at a concentration of from 1 to 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required. The compounds of the formula (I) may also be transdermally administered by the use of a skin patch.
It is to be appreciated that reference to treatment includes curative, palliative or prophylactic treatment.
Thus the invention further provides:
(i) a pharmaceutical composition comprising a compound of the formula (I) together with a pharmaceutically acceptable diluent or carrier;
(ii) a compound of the formula (I) or a pharmaceutically acceptable composition thereof, for use as a medicament;
(iii) the use of a compound of the formula (I), or of a pharmaceutically acceptable composition thereof, for the manufacture of a medicament for the treatment of a disease by producing an antagonist effect on a tachykinin receptor or on a combination of tachykinin receptors;
(iv) use as in (iii) where the antagonist effect is on the human NK1 and NK2 tachykinin receptors;
(v) use as in (iii) or (iv) where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn""s disease, a disease caused by Helicobacter pylori or another urease-positive Gram negative bacteria, a urogenital tract disorder such as incontinence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, emesis, cough, migraine or acute or chronic pain;
(vi) a method of treatment of a human to treat a disease by producing an antagonist effect on a tachykinin receptor or on a combination of tachykinin receptors, which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable composition thereof;
(vii) a method as in (vi) where the antagonist effect is on the human NK1 and NK2 tachykinin receptors;
(viii) a method as in (vi) or (vii) where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastro-intestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn""s disease, a disease caused by Helicobacter pylori or another urease-positive Gram negative bacteria, a urogenital tract disorder such as incontinence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, emesis, cough, migraine or acute or chronic pain; and
(ix) a compound of the formula (II), (XI), (XII), (XIII), (XIV), (XV), (XXIII), (XXX) or (XXXI)
with the proviso that for a compound of the formula (XXIII), when R1 is H and xe2x80x9cC1-C3 alkylenexe2x80x9d is CH2, then Ar is not 2-chlorophenyl or 2,4-dichlorophenyl.